The overall purpose of this proposal is to evaluate chemopreventive agents and surrogate markers for future clinical trials to prevent cancers in former smokers. Epidemiological studies have demonstrated a strong association between cigarette smoking and urinary bladder cancer. The chemically induced urinary bladder cancer model that we will use will allow the correlation of changes in biomarkers with the ability of the agent(s) to inhibit bladder carcinogenesis. The first specific aim will evaluate three classes of chemopreventive agents (lipoxygenase inhibitor, retinoid, and epidermal growth factor receptor (EGFr) inhibitor) either alone or in combination for efficacy in the prevention of bladder cancers. The agents are MK-886, targretin, and Iressa, respectively. We are particularly excited about the evaluation of targretin (an RXR selective retinoid) since previous studies have shown that retinoids (e.g., 4- hydroxyphenylretinamide) are active in the prevention of urinary bladder cancer. The second specific aim wilt measure the expression of survivin in urinary bladder lesions and in urine of mice treated with the carcinogen OH-BBN and/or chemopreventive agents. Specifically, we will look for survivin in early lesions of the urinary bladder; determine how quickly survivin can be detected in the urine of carcinogen-treated mice; and determine if chemopreventive agents will modulate the expression of survivin. The third specific aim will determine the effect of chemopreventive agents on gene expression profiles as assessed by Affymetrix gone chip analysis to establish new biomarkers involved in urinary bladder carcinogenesis. Examination of altered RNA levels in cancers and preneoplastic lesions in an animal model will facilitate the development of relevant surrogate biomarkers for cancer chemoprevention studies (one of the stated goals of this RFA).